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Introduction: The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016, and confirmed in its fifth edition. The biological behavior and dismal prognosis of this tumor resemble diffuse intrinsic pontine gliomas (DIPG). Homogeneously-treated series are rarely reported., Methods: From 2016 onwards, we treated patients with DMG with radiotherapy and concomitant/adjuvant nimotuzumab/vinorelbine, plus re-irradiation at relapse, as already done for DIPG., Results: We treated nine patients, seven females, with a median age at diagnosis of 13 years. Tumor sites were: thalamic in five cases, pontocerebellar in two, pineal in one, and paratrigonal with nodular/leptomeningeal dissemination in one. Three patients were biopsied, and six had partial tumor resections. Central pathological review was always performed. The median time to local progression was 12.7 months, and the median overall survival was 17.8 months. Six patients died of tumor progression, one of cerebral bleeding at progression. Two were alive, one in continuous remission, the other after relapsing, at 38.6 and 46.3 months after diagnosis. Progression-free survival was 33.3% at one year. Overall survival was 88.9%, 33.3% and 22.2% at 1, 2 and 3 years, respectively., Conclusions: This is a small series of homogeneously-treated DMG patients. The results obtained are comparable with those of DIPG patients. Given the phenotypically- and molecularly-defined setting of DMG and severe outcome in this orphan population, they should be treated and included in registries and protocols of DIPG.

Purpose: Cardiac late effects are responsible for a significant burden of mortality and morbidity among pediatric Hodgkin's lymphoma (HL) survivors (HLS). The aim of our study was to assess clinical and subclinical cardiac sequelae in a cohort of childhood HLS treated in the 1980s with doxorubicin, bleomycin, vinblastine, and dacarbazine (the ABVD regimen) and limited-field radiotherapy (RT)., Methods: We retrospectively examined a series of HLS treated from 1979 to 1989. We searched for subtle cardiac abnormalities in a subgroup of asymptomatic individuals, who underwent rest and exercise echocardiography at least 20 years after completing their therapies. Their cardiac assessment included physical examination, electrocardiogram (ECG), and resting and postexercise echocardiograms., Results: On thorough cardiac assessment a mean of 21 years after their diagnosis, none of the 53 unselected asymptomatic HLS showed physical signs or significant ECG abnormalities during or after the stress echo test. Twenty-two (41%) of the 53 patients revealed valvular abnormalities, with mitral regurgitation in 28%, aortic regurgitation in 9%, and both in 4%. No significant myocardial dysfunction as a result of previous combined doxorubicin treatment and chest RT was identified. Only 2 individuals had mild pericardial alterations., Conclusions: The present study shows that long-term cardiac effects are common in HLS treated with the ABVD regimen and RT. The most frequent complications observed in this sample were essentially coronary artery disease and valvular abnormalities. None of the survivors in this sample showed overt congestive heart failure, a finding in contrast with larger studies.

Introduction: Being able to have children could have an important positive effect on the future lives of pediatric cancer survivors. Working at a cancer institute makes us responsible for filling the gaps in our knowledge in this area of patient care., Methods: We describe our activities in a series of young females diagnosed with cancer and evaluated for fertility preservation options. We discuss the developed skills and organization as well as the practical difficulties encountered in managing fertility preservation., Results: Since September 2012, laparoscopy and cryopreservation of cortical ovarian tissue has been performed in 16 girls (with ovary transposition in 3, and after several cycles of chemotherapy in 5) and egg banking in 4 young women (before chemotherapy in 2 and several years after treatment in 2)., Conclusions: Recommendations on fertility preservation indicate that discussing the problems early on is crucial to future success. It is unthinkable to simply provide information and offer the opportunity to choose a fertility preserving technique without helping and accompanying patients and their families in their decisions and choices on the matter.

Aims: To assess the efficacy and toxicity of low-dose oral etoposide (VP) 16 in relapsing/refractory Ewing sarcoma., Methods: The records of all patients treated at our department between 1989 and 2012 for relapsing/refractory Ewing sarcoma who received oral VP-16 were analyzed. The dose was 40 mg/m2 daily for 21 consecutive days in every 28. Response was assessed after 2/3 cycles according to Response Evaluation Criteria in Solid Tumors 1.0., Results: A total of 46 of 58 patients completed at least 2 cycles; 12 suspended the treatment earlier due to rapid disease progression. The patients' median age at diagnosis was 14 years and 25/58 had metastatic disease. All patients received intensive polychemotherapy including VP-16 IV as first- (n = 53) or second-line (n = 5) treatment; 21/58 had myeloablative regimens with peripheral blood stem cell rescue, and 1 underwent allogeneic stem cell transplantation. Oral VP-16 was prescribed as 2nd-, 3rd-, and 4th-line treatment for 19, 27, and 12 patients, respectively. The cycles administered totaled 241 (median 3, mean 4 per patient; range 1-14). A total of 46 of 58 patients were evaluable: 11 responded (9 partial remission, 1 very good partial remission, 1 complete remission) and 10 were stable, the response lasting a mean of 8 months. Hematologic toxicity G3/G4 (in 164/241 evaluable cycles) occurred in 15%, 16%, and 11% of cycles for leukocytes, hemoglobin, and platelets, respectively. There were 5 cases of pneumonia. Two patients developed secondary leukemia after receiving 12 and 14 cycles., Conclusions: Low-dose oral VP-16 may be suitable in a palliative setting with an acceptable toxicity. The risk of secondary leukemia is in line with reports in the literature.

Aims and Background: Adolescent patients with cancer need psychological support in order to face the traumatic event of cancer diagnosis and to preserve continuity with their normal lives. Creative projects or laboratories may help young patients express their thoughts and feelings., Methods: The Youth Project developed activities dedicated to adolescents to give them a chance to vent their creative spirit and express themselves freely. In the first project, the teenagers designed their own fashion collection in all its various stages under the artistic direction of a well-known fashion designer, creating their own brand name (B.Live), and organized a fashion show., Results: In all, 24 patients from 15 to 20 years old took part in the project. The fashion project proved a fundamental resource in helping the young patients involved to regain a positive self-image and the feeling that they could take action, both on themselves and in their relations with others., Conclusions: Facilitating the experience of beauty may enable hope to withstand the anguish caused by disease. This experience integrated the usual forms of psychological support to offer patients a form of expression and support during the course of their treatment.

Aims and Background: Neuroblastoma is the most common solid extracranial tumor in children. The median age of onset is 2 years, with more than 95% of patients younger than 10 years at diagnosis. As neuroblastoma is rare in adolescents and exceedingly rare in adults, few series are reported in the literature. In the present study, we analyzed the outcomes and clinical characteristics of a mono-institutional series., Methods: We describe 27 consecutive patients over 12 years of age (range, 12-69) with previously untreated neuroblastoma treated at our Institution between 1982 and 2001., Results: Overall survival at 5 and 10 years was 40% and 20%, respectively, and progression-free survival at 5 and 10 years was 18%. In the present series, there was a long interval between the onset of signs/symptoms and diagnosis, and between recurrence/progression and death. None had MYCN amplification., Conclusions: The passive course of the disease in most of our patients did not reflect a more favorable outcome compared with younger patients, thus suggesting a possible genetically different subset of neuroblastoma in older patients.

Aims and Background: This study investigates the psychological status in a population of female patients who received chest irradiation for a childhood cancer and were screened for second primary breast cancer., Methods: Sixty-eight consecutive such young women were included. Compilation of the Crown-Crisp Index questionnaire was requested and 49/68 patients accepted to fill it in; 14 women in the sample had children (28%)., Results: Twenty-seven of 49 patients achieved a normal score, whereas in 22 the score was slightly above the normal range in at least one scale. Pathological scores were more frequent among the women without children., Conclusion: Quality of life in this series of long-term survivors does not seem to be severely affected by previous treatment for cancer nor by the concern for the onset of a second primary malignancy.

Purpose: The extremity site is a peculiar location for soft-tissue sarcomas (STS) of children and adolescents. Here we report the experience of the Pediatric Oncology Unit of the Istituto Nazionale Tumori of Milan, Italy, concerning 204 patients with STS of the limbs treated between 1977 and 2006., Methods: The study series included 52 patients with rhabdomyosarcoma (RMS)(65% of which were of the alveolar subtype), nine with extraosseous Ewing sarcoma and 143 with non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS), 38% of which were synovial sarcoma. Patients were treated with a multimodality approach including surgery, chemotherapy, and radiotherapy., Results: For the RMS patients, the 5-year event-free survival (EFS) rate was 37.1%, with distant metastases being the main cause of treatment failure. The outcome was particularly poor for patients with large invasive tumors, hand/foot involvement and/or nodal or distant metastases, and for patients who were not given radiotherapy. For the extraosseous Ewing sarcoma cases, 5-year EFS was 74%. For the NRSTS cases, the 5-year EFS was 72.6%: tumor size and local invasiveness, tumor grade, malignant peripheral nerve sheath tumor (MPNST) histology, and distant metastases were the main prognostic factors., Discussion: While the limbs are the most common sites of NRSTS and are often characterized by a more favorable prognosis than for axial tumors, the clinical features of extremity RMS often differ from those of RMS of other sites, with a higher incidence of unfavorable prognostic factors (e.g., alveolar subtype) and consequently unsatisfactory treatment results. The treatment of these patients is complex and necessarily multidisciplinary, and it demands not only adequate experience of treating children and adolescents in clinical trials, but also particular skills in the field of orthopedic surgery.

Aims and Background: The aim of the present study was to determine the relationship between clinico-pathologic parameters, including neuroectodermal differentiation, and their impact on survival in a series of pediatric patients with osseous tumors of the Ewing's sarcoma family admitted to the Pediatric Department of the Istituto Nazionale Tumori of Milan., Methods: Seventy-three patients were enrolled. The variables analyzed were sex, age, site of primary tumor, serum lactate dehydrogenase (LDH) level at diagnosis, involvement of periosseous soft tissues by primary tumor, presence of metastatic disease, status of disease after the treatment plan, as well as the presence of mitoses, morphologic and immunocytochemical neural markers, and neuroendocrine markers in the primary tumor., Results: Neural and neuroendocrine markers were not significantly associated with any of the other parameters. In the univariate analysis, significant risk factors related to unfavorable outcome were elevated LDH, metastatic disease, lack of complete remission after treatment, presence of mitoses and of morphological neural markers; immunocytochemical neural and neuroendocrine markers lacked prognostic value. In the multivariate analysis, only LDH levels and the status of disease following the treatment were retained., Conclusions: LDH level at diagnosis might be a useful marker to identify different risk levels; neuroectodermal differentiation might have no clear-cut impact on the clinical management of osseous Ewing's sarcoma family of tumors.

Childhood cancer is rare, representing only 1% of the total cancer problem. Of children diagnosed with cancer today, more than 70% are predicted to be long-term survivors. Essentially all pediatric cancers are treated by interdigitating radiation with surgical resection and systemic chemotherapy. The use of irradiation, important to achieve high rates of disease local control, must be always balanced against late effects specifically related to this treatment modality, principally growth retardation and second tumors induction. Using neuroblastoma, Wilms' tumor and rhabdomyosarcoma as examples, the advances in the optimal multimodality treatment of childhood cancer and the evolution of the role of radiation therapy are discussed.

Background: It remains unknown if hematopoiesis reconstituted by autografting with the sole peripheral blood hematopoietic progenitors (CPCs) after myeloablative high dose radiotherapy and/or chemotherapy is durable and capable of coping with increased demand due to boost radiotherapy, surgery, or infection., Patients and Methods: Durability of hematopoiesis was evaluated in 34 consecutive cancer patients treated with myeloablative total body irradiation (n = 17, median follow-up 3 years, range 3-49 months) and/or alkylating agent chemotherapy (n = 17, median follow-up 8 months, range 6-41 months) and autografted with CPCs because bone marrow autografting was contraindicated. CPCs (> or = 8 x 10(8) CD34+ cells/kg) had been collected during mobilization into the circulation in response to previous anticancer therapy and hematopoietic growth factor(s)., Results: Following brief temporary pancytopenia, all patients achieved normal and durable hematopoiesis. The newly reconstituted hematopoietic system was capable of reacting favorably to stressful and noxious events such as surgery, radiotherapy, or varicella-zoster infection. No secondary irreversible failure of blood cell production occurred., Conclusions: The documentation of the durability of normal hematopoiesis following myeloablative cancer therapy and autografting with mobilized CPCs implies that the latter procedure, rather than solely an alternative to bone marrow autografting, represents an advantageous tool of choice permitting substantial amelioration of the therapeutic index of high-dose cancer therapy.

To investigate the relation between estrogen receptor (ER) status and timing of relapse, we retrospectively studied two groups of patients (200 cases in each group) who underwent radical mastectomy and developed an early relapse (within 3 years of the surgery) or a long-term relapse (more than 8 years after surgery). One-hundred and eighty-two (91%) patients who developed a long-term relapse were ER-positive (ER+), whereas only 64% of patients who developed an early relapse were ER+ (P < 0.001), supporting the hypothesis that a long-term relapse is more frequently associated with an ER+ tumor. A review of the literature, which indicated that a long-term relapse arises more frequently in patients in whom a partial hormone control is maintained, seems to support this finding, albeit the presence of 18 ER-negative (ER-) cases in our study. However, this apparent contradictory observation could be explained by the fact that 12 of our patients were in premenopause and that ER-status could have been false ER- results due to the binding of endogenous estradiol to ER.